Feb. 7, 2007 -- One of the oldest treatments for a common
cause of infertility
is still the best treatment, according to findings from a study that
experts say will have a major impact on clinical practice.

The ovulation-stimulating drug clomiphene -- used in the U.S. to treat
infertility for the past four decades -- was found to be more effective than the
diabetes drug
metformin for the treatment of polycystic ovary syndrome
(PCOS) -related
infertility.

Metformin has become the leading treatment for PCOS, despite the fact that it
has not been approved for this purpose and had not been rigorously studied in
infertile patients with the disorder until now.

One brand name of metformin is Glucophage; researchers in the study used
Glucophage XR -- an extended release form of the drug.

Experts agree that the large, government-funded study proves that clomiphene
is the best first-line treatment for PCOS-related infertility.

The study appears in the Feb. 8 issue of the New England Journal of
Medicine.

"The findings are unequivocal," National Institute of
Child Health and Human
Development program director Tracy Rankin tells WebMD. "Metformin has been used
off label for years in the treatment of these patients, based largely on
anecdotal evidence that it works."

'Not as Good as We Thought'

Polycystic ovary syndrome is a leading cause of
infertility. Some studies suggest that it is the most common cause of female
infertility.

PCOS is a hormonal disorder, which can interfere with ovulation when the
ovary releases an egg. Ovaries can become enlarged and develop cysts. Women with
the disorder may also experience irregular menstrual periods and excessive body
and facial hair growth.

Obesity is also common among women with PCOS, as is the
prediabetic condition
known as insulin resistance.

The thinking has been that drugs which help sensitize the body to insulin, like
metformin, increase ovulation in women with PCOS, and, in turn, help these women
achieve viable pregnancies.

Some small studies suggested that metformin worked better than clomiphene,
which promotes ovulation by stimulating the release of specific hormones.

The newly published study included 626 infertile women with PCOS, randomly
assigned to treatment with metformin, clomiphene, or a combination of the two
drugs for up to six months. The women didn't know which exact treatment they
were getting.

Women who became pregnant were followed until delivery or pregnancy loss.

The live birth rate among the women in the study who took only metformin was
only 7%. Roughly 22% of the women who took only clomiphene gave birth, as did
27% of women who took both drugs.

"The message that this study sends is that metformin
isn't as good as we thought it was and it should definitely not be used as a
first-line, single therapy for infertility," Legro tells WebMD.

The researchers write that there were more multiple births among the
clomiphene groups (one set of triplets and four sets of twins) than the "metformin
alone" group, which had none.

Women treated with both metformin and clomiphene had higher ovulation rates
than women who took either single treatment, but they did not achieve higher
pregnancy or live-birth rates.

This seeming paradox shows, Legro says, that not all ovulations are created
equal.

"It appears that some ovulations are better than others," he says. "Clearly,
ovulation rates do not tell the whole story. Now the question becomes, 'What is
it about a clomiphene ovulation that makes it better than a metformin
ovulation?' I don't have an answer, but it certainly deserves more study."

And even though the decades-old infertility drug was proven more effective
than the diabetes drug, Legro points out that neither treatment was particularly
effective, with just over one in five women in the study giving birth.

"PCOS is a major cause of infertility, and we need new treatments that work
better than the ones we have," he says.

David S. Guzick, MD, PhD, of the University of Rochester School of Medicine,
tells WebMD that many infertility specialists who have abandoned clomiphene in
recent years will be surprised by the new findings.

"Clomiphene has been viewed by many as passe for the treatment of PCOS-related
infertility, while metformin has increasingly been seen as the drug of choice,"
he says. "But this study shows that the tried and true treatment works better."

SOURCES: Legro, R.S. The New England Journal of Medicine, Feb. 8, 2007; vol
356: pp 551-566. Richard S. Legro, MD, department of obstetrics and gynecology,
Penn State College of Medicine, Hershey, Pa. Tracy Rankin, program director,
National Institutes of Child Health and Human Development, National Institutes
of Health. David S. Guzick, MD, PhD, dean,
University of Rochester School of Medicine and Dentistry, Rochester, N.Y.